The classification of COPD based simply on magnitude of forced expiratory flow abnormality, is inadequate and of limited value in individualizing therapeutic interventions to influence the natural history of the disease. Our global hypothesis is that "COPD is a heterogeneous group of definable anatomic and physiologic disease processes, each with its own molecular and cellular processes that determine disease manifestation and progression." We propose to use 2 well established cohorts of current and former smokers to efficiently recruit and execute a cross sectional study of 800 subjects with a wide range of disease manifestation and then to follow 450 of them longitudinally over a 2-3 year course. (SA1): To use quantitative CT (QCT) determinants of airway remodeling and emphysema and their associations with other physiologic and functional indices of COPD to define unique clinicopathologic disease subclasses or phenotypes, and (SA2) To Associate Peripheral Blood Molecular and Cellular Biomarkers with Unique Clinical and Lung Histopathologic Phenotypes. We believe, based upon preliminary data, that ascertainable variation in immune cell function, cytokine expression, and genetic factors are different between and can be used to distinguish unique pathophysiologic subsets of patients. We aim nothing short of providing justification for reclassification of COPD into more biologically relevant categories that could direct development of more effective patient specific therapies. In our (SA3) we further explore the recent observations from the laboratory of our co-investigator, Dr. J Hogg, of a dramatic association between peripheral airway luminal mucous content LC% and poor survival. Findings of surrogate markers associated with this process could have immense importance because, to date, we have been unable to identify an association between the severity of LC% and any clinical or physiologic feature. We hypothesize that: Molecular and cellular biomarkers and QCT variables of COPD, in a subgroup of severe patients characterized prior to lung transplantation, are associated with severity of luminal content (LC) occlusion of peripheral airways measured in lung tissue using standard morphometric techniques. Identification of non-invasive surrogates for this condition, could have major implications in determining prognosis or targeting individual therapy.